2. Academic Validation
  3. Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3307-14. doi: 10.1016/j.bmcl.2014.06.003.
Brittney S Bates 1,  Alice L Rodriguez 1,  Andrew S Felts 1,  Ryan D Morrison 1,  Daryl F Venable 1,  Anna L Blobaum 1,  Frank W Byers 1,  Kera P Lawson 1,  J Scott Daniels 1,  Colleen M Niswender 1,  Carrie K Jones 2,  P Jeffrey Conn 1,  Craig W Lindsley 3,  Kyle A Emmitte 4
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212, USA.
  • 3 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 4 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: kyle.a.emmitte@vanderbilt.edu.
PMID: 24969015 DOI: 10.1016/j.bmcl.2014.06.003
Abstract

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and Other anxiolytics, produced dose proportional effects.

Keywords

Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5).

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